The MLH1 c.1682A>G (p.Tyr561Cys; p.Y561C) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with uncertain significance submissions.1 This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 3.10936e-06 and grpmax filtering allele frequency 8e-07, which is below the MLH1 PM2_Supporting threshold of 0.00002.2 No variant-specific calibrated functional assay result for this variant was identified in the reviewed MMR functional assay materials, so functional evidence was not used to support or refute pathogenicity.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and available in silico evidence was insufficient to assign the MLH1 missense PP3 or BP4 rules without an HCI-prior value.4
MLH1
Final classification
VUS
MLH1 c.1682A>G · p.Tyr561Cys
MLH1
The MLH1 c.1682A>G (p.Tyr561Cys; p.Y561C) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with uncertain significance submissions.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2
VUS
MLH1 c.1682A>G
PM2
→
VUS
3
vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
Gene diagram
· NM_000249.4 · variants mapped to exon structure
MLH1
NM_000249.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.10936e-06; MAF= 0.00031%, 5/1608050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33701e-05; MAF= 0.00134%, 1/74794 alleles, homozygotes = 0); grpmax FAF= 8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,608,050
0 hom · FAF 8e-05%
0 hom · FAF 8e-05%
African/African American 1 / 74,794 |
0.0013% |
European (non-Finnish) 4 / 1,174,522 |
0.00034% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 1 / 31,396
0 hom
0 hom
African/African American 1 / 8,712 |
0.011% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links